Defining the molecular pathological events underlying the selective vulnerability of neuron populations associated with cognitive decline during the progression of Alzheimer's disease (AD) is crucial for biomarker development and therapeutics to slow/prevent the onset of this disease. Project 4 of this Program Project provided novel insights into the neurotrophic mechanisms underlying the survival of the cholinergic basal forebrain (CBF) neurons, which provide the cholinergic innervation the entire cortical mantle and hippocamppus, play a key role in memory and attention, their degeneration is associated with clinical severity and disease duration as well as targets of drug therapies during the onsest of AD. This area gained greater importance following a recent Phase 1 clinical trial demonstrating that ex vivo NGF (CBF neuron survival factor) gene therapy improves cognition and induces CBF neuronal sprouting in mild AD. Our striking findings showing a shift in the balance between cell survival and cell death mechanisms, a phenotypic reduction in trkA and p75NTR but not ChAT containing CBF neurons as well as a shift in the ratio of 3Rtau/4Rtau within CBF neurons in people with mild cogntivie impairment suggest that subtle alterations in the balance of cellular molecules underlie CBF neuron death. The pro-apoptotic effect(s) of p75NTRmediated proNGF signaling is, in part, dependent on its interactions with the chaperone neurotensin receptor, sortilin, which we have shown to increase in the AD cortex (see Preliminary data) suggest a role in CBF cell death in AD. Project Specific Aims will test the following hypothesis: 1 A. that cortical sortilin level is increased in the MCI and AD compared to NCI cortex. 1B. that TrkA is increased while p75NTR, sortilin and proNGF protein levels remain stable in hippocampus in MCI (see Preliminary data). 2A. that there are greater numbers of ChAT only immunopositive nucleus basalis neurons compared of co-labeled for ChAT and NGF receptors. 2B. that classes of genes for cell survival signaling, regulation of transcription, and cholinergic neurotransmission are differentially altered in ChAT only compared to those co-labeled also for ChAT and TrkA or p75NTR during the progression of AD. 3. that alteration in the expression ratio of 3Rtau/4Rtau isoforms is an early marker in the evolution of CBF NFTs during the progression of AD. These findings will directly translate to the development of new drugs for CBF cell survival in MCI and AD.